We investigated the cognitive and neural bases of impaired speech fluency, a central feature of primary progressive aphasia. Speech fluency was assessed in 35 patients with frontotemporal lobar degeneration (FTLD) who presented with progressive non-fluent aphasia (PNFA, n=11), semantic dementia (SemD, n=12), or a social and executive disorder without aphasia (SOC/EXEC, n=12). Fluency was quantified as the number of words per minute in an extended, semi-structured speech sample. This was related to language characteristics of the speech sample and to neuropsychological measures. PNFA patients were significantly less fluent than controls and other FTLD patients. Fluency correlated with grammatical expression but not with speech errors or executive difficulty. SemD and SOC/EXEC patients were also less fluent than controls. In SemD, fluency was associated with semantically limited content. In SOC/EXEC, fluency was associated with executive limitations. Voxel-based morphometry analyses of high-resolution MRI related fluency to gray matter volume in left inferior frontal, insula, and superior temporal regions for the entire cohort of FTLD patients. This region overlapped partially distinct atrophic areas in each FTLD subgroup. It thus appears to play a crucial role in speech fluency, which can be interrupted in different ways in different FTLD subgroups.

Objective: To investigate the neural basis for the behavioral symptoms of frontotemporal lobar degeneration (FTLD) that cause the greatest caregiver distress. Background: FTLD is a progressive neurodegenerative disease associated with behavioral disturbances. Group studies have related these behaviors to volume loss on MRI. Methods: Forty caregivers of patients with the clinical diagnosis of FTLD completed the Neuropsychiatric Inventory. Twelve neuropsychiatric symptoms and the associated caregiver distress were assessed. Optimized voxel-based morphometry identified significant atrophy in subgroups of FTLD patients with isolated behavioral symptoms corresponding to the most distressing behaviors, and we correlated cortical atrophy directly with these distressing behavioral disorders in an unbiased group analysis. Results: The greatest stressors for caregivers were apathy and disinhibition (p < 0.005 for both contrasts). Partially distinct areas of cortical atrophy were associated with these behaviors in both individual patients with these symptoms and group-wide analyses, including the dorsal anterior cingulate cortex and dorsolateral prefrontal cortex in apathetic patients, and the medial orbital frontal cortex in disinhibited patients. Conclusions: Caregiver stress in families of FTLD patients is due in large part to apathy and disinhibition. The anatomic distribution of cortical loss corresponding to these distressing social behaviors includes partially distinct areas within the frontal lobe.

To investigate the basis for impaired sentence comprehension in patients with frontotemporal dementia (FTD) we assessed grammatical comprehension and verbal working memory in 88 patients with three distinct presentations: progressive nonfluent aphasia (PNFA), semantic dementia (SD), and nonaphasic patients with a disorder of social comportment and executive processing (SOC/ EXEC). We related sentence comprehension and working memory performance to regional cortical volume in a subgroup of 29 patients with structural MRI scans using voxel-based morphometry. PNFA patients exhibited the greatest difficulty with sentence comprehension and were especially impaired with grammatically complex sentences, which correlated with atrophy in left inferior frontal cortex. Working memory performance in these same patients correlated with a proximal but distinct left inferior frontal region. SD patients' sentence comprehension scores correlated with left inferolateral temporal lobe damage, which we hypothesize and reflect impairments in lexical processing. We did not observe any consistent relationship between cortical atrophy and sentence comprehension impairment in SOC/EXEC patients, suggesting the deficits in this subgroup may be due to more variable declines in executive resources.

Background-The natural history of patients with pathologically proven frontotemporal lobar degeneration (FTLD) is important from clinical and biologic perspectives, but is not well documented quantitatively.

Patients with semantic dementia (SD) have a striking impairment in semantic memory, but the basis for this deficit is unclear. We examined semantic memory for concrete and abstract verbs with a two-alternative, forced-choice measure of lexical semantic associative knowledge. Patients with SD had significantly greater difficulty with concrete verbs (z = −3.33) than abstract verbs (z = −2.05), a “reversal of the concreteness effect” that was present in a majority of individual patients. The subgroup of SD patients with imaging had significant cortical thinning in the anterior and inferolateral portions of the temporal lobes. These areas of visual association cortex may be important for storing and processing visual features for word meaning. Moreover, poor performance with concrete relative to abstract verbs correlated with cortical thinning of the right anterior temporal lobe in SD, suggesting that this region may contribute to storing and processing visual semantic features. These observations raise the possibility that degraded visual feature knowledge contributes in part to the impaired comprehension of concrete words in SD.

Few studies have assessed whether the patterns of neuropsychological impairment in patients with different frontotemporal lobar degeneration (FTLD) subtypes remain distinct over the duration of their illness or devolve into a common, undifferentiated neuropsychological state. A longitudinal neuropsychological analysis was obtained over 100 months assessing executive control, language/ naming, and visuoconstruction in 441 patients diagnosed with Alzheimer's disease (AD) and four FTLD subtypes, i.e., a social comportment/dysexecutive (SOC/EXEC) disorder; progressive nonfluent aphasia (PNFA); semantic dementia (SemD); and corticobasal degeneration (CBD). Initial group differences on each measure were maintained over the duration of illness, including several double dissociations. For example, AD patients exhibited a decline in 'animal' fluency; PNFA Correspondence concerning this article should be addressed to David J. Libon, Department of Neurology, Drexel University College of Medicine, Philadelphia, PA 19129. E-mail: dlibon@drexelmed.edu. NIH Public Access Author ManuscriptNeuropsychology. Author manuscript; available in PMC 2010 May 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript patients had difficulty on tests of executive control, SemD maintained their impairment on tests of naming, and CBD had presented with performance on visuoconstructional tests. None of the group by neuropsychological task interactions evaluating longitudinal decline was significant, suggesting that performance does not converge onto a common subtype over time. These data indicate that distinct patterns of neuropsychological impairment are maintained longitudinally, reflecting the unique anatomic distribution of relative disease burden in AD and FTLD.Keywords frontotemporal dementia; Alzheimer's disease; longitudinal assessmentFrontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative illness presenting with imaging and autopsy evidence of frontal and temporal alterations (McKhann et al., 2001;Snowden, Neary, & Mann, 1996). Major FTLD subtypes that have been identified include a social/dysexecutive (SOC/EXEC) syndrome, progressive nonfluent aphasia (PNFA), semantic dementia (SemD), and corticobasal degeneration (CBD). In this study, we examined the longitudinal course of the neuropsychological profiles of these patient groups to determine whether their initial neuropsychological deficits are maintained over time, or whether these distinctions are lost as the disease progresses such that they merge into a single, end-stage clinical dementia profile. This issue has clinical as well as theoretical implications.Past neuropsychological studies have tended to focus on the initial, cross-sectional differences that may distinguish FTLD from Alzheimer's disease (AD; Kramer et al., 2003;Libon, Massimo, et al., 2007;Libon, Xie, et al., 2007). For example, Libon, Massimo, et al. (2007) studied a large sample of AD and FTLD patients and subjected their performance on a comprehensive neuropsychol...

We used an online word-monitoring paradigm to examine sentence processing in healthy seniors and frontotemporal dementia patients with progressive nonfluent aphasia (PNFA) or a nonaphasic disorder of social and executive functioning (SOC/EXEC). Healthy seniors were sensitive to morphosyntactic, major grammatical subcategory, and selection restriction violations in a sentence. PNFA patients were insensitive to grammatical errors, but showed reasonable sensitivity to thematic matrix violations, consistent with a differential grammatical processing impairment. By contrast, SOC/EXEC patients showed partial sensitivity to grammatical errors but were insensitive to thematic violations. These findings support a dissociation between grammatical and thematic components of sentence processing. Specifically, they are consistent with a grammatical processing deficit in PNFA patients, and impairment in the formation of a coherent thematic matrix in SOC/EXEC patients.

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